Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance (2012) & ECETOC (2010)
Overall assessment factor (AF):
20.4
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
261.72 mg/m³
Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

--

- 0.38 m³/kg Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012)

- Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (ECHA R.8, 2012)

- Standard route-to-route extrapolation factor oral to inhalation of 2 (ECHA R.8, 2012). This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

--

Standard route-to-route extrapolation factor oral to dermal of 1 (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012) and oral absorption is indicated to be significantly higher as indicated by physico-chemical parameters.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with 1,4-BDDMA (analogous substance of 1,6-HDDMA) in rats

 

DNEL inhal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kg bw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

0.38 m³/kg

 

6.7 m3/10 m3

Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012)

-Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required(ECHA R.8, 2012)

 

Route-to-Route extrapolation

2

Oral to inhalation extrapolation (ECHA R.8, 2012) This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

NAEC worker

264.6 mg/m3

 

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)

Intraspecies

3

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on a subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

14.5 mg/m3

Using a total factor (POD modifier and AF) of 20.4 (/ 0.38 x 10/6.7 m³ x 2 x 1 x 3 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, workerof 14.5 mg/m³ is derived.

 

 

DNEL dermal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kg bw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

1

Oral to dermal extrapolation (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012) and oral absorption is indicated to be significantly higher as indicated by physico-chemical parameters (see above)

NAEL worker

300 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans (ECHA R.8, 2012)

Intraspecies

3

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

4.2 mg/kg bw/d

Using a total factor (POD modifier and AF) of 72 (1 x 4 x 3 x 6 x 1 x 1) a DNELlong-term, dermal, workerof 4.2 mg/kg bw/d is derived.

Further considerations

AF for remaining differences based on analysis of the toxicological relevant metabolites of 1,6-HDDMA and 1,4-BDDMA

 

There is a high likelihood that 1,6-HDDMA, like other members of the category, is rapidly metabolized to the metabolites MAA and 1,6-HD within the order of minutes (see category document). Thus, systemic toxicity levels of the metabolites were compared to find out the toxicological relevant metabolite in order to evaluate remaining differences regarding the read across from 1,4-BDDMA to 1,6-HDDMA. .

The methacrylic metabolite MAA is the common metabolite for 1,6-HDDMA and 1,4-BDDMA and thus cannot be used for differentiation. The NOAEL for oral repeated dose toxicity of MMA, (i.e. 124 mg/kg bw/d; Borzelleca 1964) corresponds to 1.24 mM MAA/ kg bw/d on molar basis.

With respect to the metabolites, the toxicity of the different alcohol moieties can be understood as “remaining uncertainty” for the DNEL assessment. Regarding the different alcohol metabolites, 1,4-BD has a clear toxicological profile (neurobehaviour) which was not observed for 1,6-HD. Accordingly, the NOAEL for oral repeated dose toxicity of 1,4-BD, (i.e. 225 mg gamma-BL/kg bw/d in male rats; NTP 1992/1996) corresponds to 2.6 mM 1,4-BD/ kg bw/d on molar basis, while the NOEL for oral repeated dose toxicity of 1,6-HD, (i.e. 1000 mg 1,6-HD/kg bw/d in rats; NTP BASF 1995) corresponds to a clearly higher level of 8,5 mM 1,6-HD/ kg bw/d on molar basis.

Thus, due to the lowest NOAEL level in repeated dose studies, it can be concluded that the common methacrylic metabolite MAA is the toxicological relevant metabolite for both substances, especially as two molecules of MAA will be produced by one molecule 1,6 -HDDMA during hydrolysis.

Moreover, the alcohol moiety in 1,6-HDDMA is less systemic toxic in comparison to 1,4-BDDMA. As a consequence, there is no remaining difference to be considered for the read across from 1,4-BDDMA to 1,6-HDDMA, leading to a AF of “1”.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
69
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
130.21 mg/m³
Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

--

- 1.15 m³/kg Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012)

- Standard route-to-route extrapolation factor oral to inhalation of 2 (ECHA R.8, 2012). This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

--

Standard route-to-route extrapolation factor oral to dermal of 1 (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012) and oral absorption is indicated to be significantly higher as indicated by physico-chemical parameters.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation required
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, 2012).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Sytemic effects, long term

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with 1,4-BDDMA (analogous substance of 1,6-HDDMA) in rats

 

DNEL inhal gen pop long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kg bw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

1.15 m³/kg

Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012)

Route-to-Route extrapolation

2

Oral to inhalation extrapolation (ECHA R.8, 2012). This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

NAEC general population

130.5 mg/m3

 

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)

Intraspecies

5

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

4.3 mg/m3

Using a total factor (POD modifier and AF) of 69 (/ 1.15 m³ x 2 x 1 x 5 x 6 x 1 x 1 x 1) a DNELlong-term,inhal, gen. pop.of 4.3 mg/m³ is derived.

  

 

DNEL dermal general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kg bw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

1

Oral to dermal extrapolation (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012) and oral absorption is indicated to be significantly higher (see above)

NAEL general population

300 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans (ECHA R.8, 2012)

Intraspecies

5

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

2.5 mg/kg bw/d

Using a total factor (POD modifier and AF) of 120 (1 x 4 x 5 x 6 x 1 x 1) a DNELlong-term,dermal, gen.pop.of 2.5 mg/kg bw/d is derived.

   

 

DNEL oral general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kgbw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

1

No route-to-route extrapolation required.

NAEL general population

300 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans (ECHA R.8, 2012)

Intraspecies

5

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (1,4- -BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA does not indicate remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

2.5 mg/kg bw/d

Using a total factor (POD modifier and AF) of 120 (1 x 4 x 5 x 6 x 1 x 1) a DNELlong-term,oral, gen.pop.of 2.5 mg/kg bw/d is derived.

 

Further considerations

AF for remaining differences based on analysis of the toxicological relevant metabolites of 1,6-HDDMA and 1,4-BDDMA

 

There is a high likelihood that 1,6-HDDMA, like other members of the category, is rapidly metabolized to the metabolites MAA and 1,6-HD within the order of minutes (see category document). Thus, systemic toxicity levels of the metabolites were compared to find out the toxicological relevant metabolite in order to evaluate remaining differences regarding the read across from 1,4-BDDMA to 1,6-HDDMA. .

The methacrylic metabolite MAA is the common metabolite for 1,6-HDDMA and 1,4-BDDMA and thus cannot be used for differentiation. The NOAEL for oral repeated dose toxicity of MMA, (i.e. 124 mg/kg bw/d; Borzelleca 1964) corresponds to 1.24 mM MAA/ kg bw/d on molar basis.

With respect to the metabolites, the toxicity of the different alcohol moieties can be understood as “remaining uncertainty” for the DNEL assessment. Regarding the different alcohol metabolites, 1,4-BD has a clear toxicological profile (neurobehaviour) which was not observed for 1,6-HD. Accordingly, the NOAEL for oral repeated dose toxicity of 1,4-BD, (i.e. 225 mg gamma-BL/kg bw/d in male rats; NTP 1992/1996) corresponds to 2.6 mM 1,4-BD/ kg bw/d on molar basis, while the NOEL for oral repeated dose toxicity of 1,6-HD, (i.e. 1000 mg 1,6-HD/kg bw/d in rats; NTP BASF 1995) corresponds to a clearly higher level of 8,5 mM 1,6-HD/ kg bw/d on molar basis.

Thus, due to the lowest NOAEL level in repeated dose studies, it can be concluded that the common methacrylic metabolite MAA is the toxicological relevant metabolite for both substances, especially as two molecules of MAA will be produced by one molecule 1,6 -HDDMA during hydrolysis.

Moreover, the alcohol moiety in 1,6-HDDMA is less systemic toxic in comparison to 1,4-BDDMA. As a consequence, there is no remaining difference to be considered for the read across from 1,4-BDDMA to 1,6-HDDMA, leading to a AF of “1”.